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A high pressure refolding technology developed and patented by Dr. Ted Randolph of the CU Boulder Department of Chemical and Biological Engineering, Dr, John Carpenter of the CU School of Pharmacy, and CU graduate students, is being used to produce an improved drug treatment for multiple sclerosis patients. The technology was licensed to BaroFold Inc. who developed the interferon-beta drug product through phase I clinical trials and then licensed it to Nuron BioTech Inc.
Full text A group of researchers led by Dr. Krishna M. G. Mallela is discovering how a deficiency of functional dystrophin protein in muscle cells causes muscular dystrophy.
Full text University of Colorado is part of an expanding worldwide effort to fight the deadly human immunodeficiency virus on a new front: preventing its transmission in people not yet infected by the virus.
Full text 08/16/2010
Life Science Weekly
Research findings, 'Effects of lipid-lowering therapy on reduction of cardiovascular events in patients with end-stage renal disease requiring hemodialysis,' are discussed in a new report. According to recent research from the United States, "In the general population, dyslipidemia is an established independent risk factor for cardiovascular disease. In patients with end-stage renal disease (ESRD), comorbid cardiovascular disease is present at alarming rates, and those who require hemodialysis and have cardiovascular disease continue to have a high mortality rate."
"Lipid abnormalities associated with chronic kidney disease (CKD) vary depending on the stage of disease (stages 1-5), but low-density lipoprotein cholesterol (LDL) has been established as the primary lipid treatment target. Guidelines support an LDL level of less than 100 mg/dl in patients with all stages of CKD, except when the triglyceride level is above 500 mg/dl. As patients progress to stage 5 CKD (ESRD with hemodialysis), the high triglyceride, low high-density lipoprotein cholesterol, and increased lipoprotein(a) levels of the early stages become more pronounced, with increases in small dense LDL particles; however, total cholesterol and LDL values remain normal or decrease. In patients undergoing hemodialysis, lipid abnormalities are driven by an increase in hepatic secretion and delayed catabolism of very low-density lipoproteins, as well as a reduction in lipoprotein lipase and hepatic lipase. Epidemiologic data support the role of cholesterol lowering as a means to lower cardiovascular events in the hemodialysis population. We conducted a literature search of various databases (1966-September 2009) to identify relevant clinical trials that evaluated the efficacy and safety of multiple lipid-lowering agents for the treatment of dyslipidemia in patients with ESRD requiring hemodialysis. Only those trials that used clinical primary end points of coronary heart disease (e.g., cardiovascular death, myocardial infarction, stroke) were included in this review. Evidence demonstrates that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy (i.e., atorvastatin and rosuvastatin) significantly reduces surrogate cardiovascular markers, particularly LDL, in patients with ESRD requiring hemodialysis; however, no statin has proved to reduce cardiovascular morbidity or mortality in this population. Trials evaluating omega-3 fatty acids did not show significant reductions in LDL or cardiovascular events in this population," wrote J.C. Marrs and colleagues, University of Colorado, Department of Clinical Pharmacy (see also ).
The researchers concluded "Clinicians should appreciate these limitations when deciding whether to continue lipid-lowering pharmacotherapy in these patients, depending on their overall cardiovascular risk assessment."
Marrs and colleagues published their study in Pharmacotherapy (Effects of lipid-lowering therapy on reduction of cardiovascular events in patients with end-stage renal disease requiring hemodialysis. Pharmacotherapy, 2010;30(8) 823-9).
For additional information, contact J.C. Marrs, University of Colorado, Dept. of Clinical Pharmacy, School of Pharmacy, Aurora, CO 80045 USA.
Publisher contact information for the journal Pharmacotherapy is IOS Press, Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands.
Copyright © 2010 Life Science Weekly via NewsRx.com Dr. Rajesh Agarwal was interviewed by the Denver Post for a piece on the benefits of broccoli sprouts.
Full text From Rwanda to America, a CU pharmacy grad’s journey, the Aurora Sentinel, June 3, 2010. Freddy Kaniki is ready to begin the next chapter in the new life he’s created for his family after graduating from the University of Colorado School of Pharmacy
Full text Dr. Rajesh Agarwal was interviewed by the Denver Post for a piece on the benefits of broccoli sprouts.
Full text From Rwanda to America, a CU pharmacy grad’s journey, the Aurora Sentinel, June 3, 2010. Freddy Kaniki is ready to begin the next chapter in the new life he’s created for his family after graduating from the University of Colorado School of Pharmacy
Full text 07/19/2010
Life Science Weekly
New research, 'Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation,' is the subject of a report. "Alveolar macrophages and BDMCs undergo sequential biochemical changes during the chronic inflammatory response to chemically induced lung carcinogenesis in mice. Herein, we examine two chronic lung inflammation models-repeated exposure to BHT and infection with Mycobacterium tuberculosis-to establish whether similar macrophage phenotype changes occur in non-neoplastic pulmonary disease," scientists in the United States report (see also ).
"Exposure to BHT or M. tuberculosis results in pulmonary inflammation characterized by an influx of macrophages, followed by systemic effects on the BM and other organs. In both models, pulmonary IFN-gamma and IL-4 production coincided with altered polarization of alveolar macrophages. Soon after BHT administration or M. tuberculosis infection, IFN-gamma content in BALF increased, and BAL macrophages became classically (M1) polarized, as characterized by increased expression of iNOS. As inflammation progressed in both models, the amount of BALF IFN-gamma content and BAL macrophage iNOS expression decreased, and BALF IL-4 content and macrophage arginase I expression rose, indicating alternative/M2 polarization. Macrophages present in M. tuberculosis-induced granulomas remained M1-polarized, implying that these two pulmonary macrophage populations, alveolar and granuloma-associated, are exposed to different activating cytokines. BDMCs from BHT-treated mice displayed polarization profiles similar to alveolar macrophages, but BDMCs in M. tuberculosis-infected mice did not become polarized," wrote E.F. Redente and colleagues, University of Colorado, Department of Pharmaceutical Sciences.
The researchers concluded "Thus, only alveolar macrophages in these two models of chronic lung disease exhibit a similar progression of polarization changes; polarization of BDMCs was specific to BHT-induced pulmonary inflammation, and polarization of granuloma macrophages was specific to the M. tuberculosis infection."
Redente and colleagues published their study in the Journal of Leukocyte Biology (Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation. Journal of Leukocyte Biology, 2010;88(1) 159-68).
For more information, contact E.F. Redente, University of Colorado Denver, Dept. of Pharmaceutical Sciences, Aurora, CO 80045 USA.
Copyright © 2010 Life Science Weekly via NewsRx.com 07/16/2010
Obesity, Fitness & Wellness Week
New investigation results, 'Teriflunomide (leflunomide) promotes cytostatic, antioxidant, and apoptotic effects in transformed prostate epithelial cells evidence supporting a role for teriflunomide in prostate cancer chemoprevention,' are detailed in a study published in Neoplasia. According to a study from the United States, "Teriflunomide (TFN) is an inhibitor of de novo pyrimidine synthesis and the active metabolite of leflunomide. Leflunomide is prescribed to patients worldwide as an immunomodulatory and anti-inflammatory disease-modifying prodrug."
"Leflunomide inhibited the growth of human prostate cancer xenographs in mice, and leflunomide or TFN promoted cytostasis and/or apoptosis in cultured cells. These findings suggest that TFN could be useful in prostate cancer chemoprevention. We investigated the possible mechanistic aspects of this tenet by characterizing the effects of TFN using premalignant PWR-1E and malignant DU-145 human prostate epithelial cells. TFN promoted a dose-and time-dependent cytostasis or apoptosis induction in these cells. The cytostatic effects of TFN, which were reversible but not by the presence of excess uridine in the culture medium, included diminished cellular uridine levels, an inhibition in oxygen consumption, a suppression of reactive oxygen species (ROS) generation, S-phase cell cycle arrest, and a conspicuous reduction in the size and number of the nucleoli in the nuclei of these cells. Conversely, TFN's apoptogenic effects were characteristic of catastrophic mitochondrial disruption (i.e., a dissipation of mitochondrial inner transmembrane potential, enhanced ROS production, mitochondrial cytochrome c release, and cytoplasmic vacuolization) and followed by DNA fragmentation. The respiration-deficient derivatives of the DU-145 cells, which are also uridine auxotrophs, were markedly resistant to the cytostatic and apoptotic effects of TFN, implicating de novo pyrimidine synthesis and mitochondrial bioenergetics as the primary targets for TFN in the respiration competent cells," wrote N. Hail and colleagues, University of Colorado, Department of Pharmaceutical Sciences (see also ).
The researchers concluded "These mechanistic findings advocate a role for TFN and mitochondrial bioenergetics in prostate cancer chemoprevention."
Hail and colleagues published their study in Neoplasia (Teriflunomide (leflunomide) promotes cytostatic, antioxidant, and apoptotic effects in transformed prostate epithelial cells evidence supporting a role for teriflunomide in prostate cancer chemoprevention. Neoplasia, 2010;12(6) 464-75).
For more information, contact N. Hail, University of Colorado Denver School of Pharmacy, Dept. of Pharmaceutical Sciences, 12700 E 19th Avenue, Aurora, CO 80045 USA.
Copyright © 2010 Obesity, Fitness & Wellness Week via NewsRx.com 07/13/2010
Biotech Week
Research findings, 'Biological and molecular mechanisms of sulfur mustard analogue-induced toxicity in JB6 and HaCaT cells possible role of ataxia telangiectasia-mutated/ataxia telangiectasia-Rad3-related cell cycle checkpoint pathway,' are discussed in a new report. "Effective medical treatment and preventive measures for chemical warfare agent sulfur mustard (HD)-caused incapacitating skin toxicity are lacking, because of limited knowledge of its mechanism of action. The proliferating basal epidermal cells are primary major sites of attack during HD-caused skin injury," scientists in the United States report (see also ).
"Therefore, employing mouse JB6 and human HaCaT epidermal cells, here, we investigated the molecular mechanism of HD analogue 2-chloroethyl ethyl sulfide (CEES)-induced skin cytotoxicity. As compared to the control, up to 1 mM CEES treatment of these cells for 2, 4, and 24 h caused dose-dependent decreases in cell viability and proliferation as measured by DNA synthesis, together with S and G2-M phase arrest in cell cycle progression. Mechanistic studies showed phosphorylation of DNA damage sensors and checkpoint kinases, ataxia telangiectasia-mutated (ATM) at ser1981 and ataxia telangiectasia-Rad3-related (ATR) at ser428 within 30 min of CEES exposure, and modulation of S and G2-M phase-associated cell cycle regulatory proteins, which are downstream targets of ATM and ATR kinases. Hoechst-propidium iodide staining demonstrated that CEES-induced cell death was both necrotic and apoptotic in nature, and the latter was induced at 4 and 24 h of CEES treatment in HaCaT and JB6 cells, respectively. An increase in caspase-3 activity and both caspase-3 and poly(ADP-ribose)polymerase (PARP) cleavage coinciding with CEES-caused apoptosis in both cell lines suggested the involvement of the caspase pathway. Together, our findings suggest a DNA-damaging effect of CEES that activates ATM/ATR cell cycle checkpoint signaling as well as caspase-PARP pathways, leading to cell cycle arrest and apoptosis/necrosis in both JB6 and HaCaT cells," wrote N. Tewari-Singh and colleagues, University of Colorado, Department of Pharmaceutical Sciences.
The researchers concluded "The identified molecular targets, quantitative biomarkers, and epidermal cell models in this study have the potential and usefulness in rapid development of effective prophylactic and therapeutic interventions against HD-induced skin toxicity."
Tewari-Singh and colleagues published their study in Chemical Research In Toxicology (Biological and molecular mechanisms of sulfur mustard analogue-induced toxicity in JB6 and HaCaT cells possible role of ataxia telangiectasia-mutated/ataxia telangiectasia-Rad3-related cell cycle checkpoint pathway. Chemical Research In Toxicology, 2010;23(6) 1034-44).
For additional information, contact N. Tewari-Singh, University of Colorado Denver, Dept. of Pharmaceutical Sciences, School of Pharmacy, 12700 East 19th Avenue, Box C238 P-15, Research 2, Aurora, Colorado 80045 USA. Copyright
© 2010 Biotech Week via NewsRx.com 07/12/2010
Science Letter
Research findings, 'Human aldehyde dehydrogenase genes alternatively spliced transcriptional variants and their suggested nomenclature,' are discussed in a new report. According to recent research published in the journal Pharmacogenetics and Genomics, "The human aldehyde dehydrogenase (ALDH) gene superfamily consists of 19 genes encoding enzymes critical for NAD(P)-dependent oxidation of endogenous and exogenous aldehydes, including drugs and environmental toxicants. Mutations in ALDH genes are the molecular basis of several disease states (e.g."
"Sjogren-Larsson syndrome, pyridoxine-dependent seizures, and type II hyperprolinemia) and may contribute to the etiology of complex diseases such as cancer and Alzheimer's disease. The aim of this nomenclature update was to identify splice transcriptional variants principally for the human ALDH genes. Data-mining methods were used to retrieve all human ALDH sequences. Alternatively spliced transcriptional variants were determined based on (i) criteria for sequence integrity and genomic alignment; (ii) evidence of multiple independent cDNA sequences corresponding to a variant sequence; and (iii) if available, empirical evidence of variants from the literature. Alternatively spliced transcriptional variants and their encoded proteins exist for most of the human ALDH genes; however, their function and significance remain to be established. When compared with the human genome, rat and mouse include an additional gene, Aldh1a7, in the ALDH1A subfamily. To avoid confusion when identifying splice variants in various genomes, nomenclature guidelines for the naming of such alternative transcriptional variants and proteins are recommended herein," wrote W.J. Black and colleagues, University of Colorado, Department of Pharmaceutical Sciences (see also ).
The researchers concluded "In addition, a web database (www.aldh.org) has been developed to provide up-to-date information and nomenclature guidelines for the ALDH superfamily."
Black and colleagues published their study in Pharmacogenetics and Genomics (Human aldehyde dehydrogenase genes alternatively spliced transcriptional variants and their suggested nomenclature. Pharmacogenetics and Genomics, 2009;19(11) 893-902).
For additional information, contact W.J. Black, University of Colorado Denver, University of Colorado Denver, Dept. of Pharmaceutical Sciences, Aurora, Colorado 80045 USA.
Copyright © 2010 Science Letter via NewsRx.com
07/09/2010
Obesity, Fitness & Wellness Week
Current study results from the report, 'NAD(P)H quinone oxidoreductase 1-compromised human bone marrow endothelial cells exhibit decreased adhesion molecule expression and CD34+ hematopoietic cell adhesion,' have been published. "NAD(P)H quinone oxidoreductase 1 (NQO1) deficiency resulting from a homozygous NQO1*2 polymorphism has been associated with an increased risk of benzene-induced myeloid toxicity and a variety of de novo and therapy-induced leukemias. Endothelial cells in human bone marrow form one of the two known hematopoietic stem cell microenvironments and are one of the major cell types that express NQO1 in bone marrow," researchers in the United States report (see also ).
"We have used a transformed human bone marrow endothelial cell (TrHBMEC) line to study the potential impact of a lack of NQO1 activity on adhesion molecule [endothelial leukocyte adhesion molecule 1 (E-selectin), vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1] expression and functional adhesion to bone marrow progenitor cells. We used both 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a mechanism-based inhibitor of NQO1, and anti-NQO1 small interfering RNA to abrogate NQO1 activity. Real-time reverse transcription-polymerase chain reaction data demonstrated a significant inhibition of tumor necrosis factor (TNF)alpha-induced E-selectin mRNA levels after ES936 pretreatment. Immunoblot assays demonstrated a significant reduction in TNF-alpha-stimulated E-selectin, VCAM-1, and ICAM-1 proteins after inhibition or knockdown of NQO1. The mechanisms underlying this effect remain undefined, but modulation of nuclear factor-kappaB (p65), c-Jun, and activating transcription factor 2, transcriptional regulators of adhesion molecules, were observed after inhibition or knockdown of NQO1. Decreased level of E-selectin, VCAM-1, and ICAM-1 also resulted in a functional deficit in adhesion. A parallel plate flow chamber study demonstrated a marked reduction in CD34(+) cell (KG1a) adhesion to NQO1-deficient TrHBMECs relative to controls," wrote H. Zhou and colleagues, University of Colorado, Department of Pharmaceutical Sciences.
The researchers concluded "The reduced adhesive ability of TrHBMECs may affect the function of the vascular stem cell niche and also may contribute to the increased susceptibility of polymorphic individuals lacking NQO1 to leukemias and hematotoxicants such as benzene."
Zhou and colleagues published their study in the Journal of Pharmacology and Experimental Therapeutics (NAD(P)H quinone oxidoreductase 1-compromised human bone marrow endothelial cells exhibit decreased adhesion molecule expression and CD34+ hematopoietic cell adhesion. Journal of Pharmacology and Experimental Therapeutics, 2010;334(1) 260-8).
For additional information, contact H. Zhou, University of Colorado Denver, Dept. of Pharmaceutical Sciences, School of Pharmacy, Anschutz Medical Campus, Aurora, CO 80045 USA.
Copyright © 2010 Obesity, Fitness & Wellness Week via NewsRx.com
Professor and interim chair of the Department of Clinical Pharmacy, Doug Fish, PharmD, recently accepted and assumed the role of Department Chair.
A clinical associate professor in the School of Medicine, Division of Pulmonary Sciences/Critical Care Medicine, Dr. Doug Fish is a clinical specialist in infectious diseases and critical care at the University of Colorado Hospital in Denver. Fish completed his doctor of pharmacy at the University of California at San Francisco, a clinical pharmacy residency at Duke University Medical Center, and a fellowship in infectious disease/critical care at the University of Illinois at Chicago. He has been in Colorado since 1992.
Active in many state and national professional societies, Dr. Fish is a fellow of the American College of Critical Care Medicine and the American College of Clinical Pharmacy, a past president of the Society of Infectious Diseases Pharmacists, and also served as president of the Colorado Pharmacists Society. He is a board-certified pharmacotherapy specialist (BCPS) with added qualifications in infectious diseases. His research interests primarily concern antimicrobial pharmacokinetics and pharmacodynamics, use of antimicrobials in critically ill and immunocompromised patients, and antimicrobial resistance.
Dr. Fish's Faculty Page
Chair's Page, Department of Clinical Pharmacy Two University of Colorado’s School of Pharmacy researchers have been named American Association for the Advancement of Science (AAAS) Pharmaceutical Sciences fellows and a third has been elected as a fellow of the Association for Research in Vision and Ophthalmology (ARVO). Raj Agarwal, PhD, and John Carpenter, PhD, are two of only eight Pharmaceutical Sciences AAAS fellows elected in 2009. Uday Kompella, PhD, will be awarded ARVO fellow status in 2010.
Full text. The Michael J. Fox Foundation for Parkinson's Research (MJFF) recently announced $1.5 million in total awards to six research teams, including an Associate Professor from University of Colorado’s School of Pharmacy, who are working to develop potentially disease-modifying therapies for Parkinson's disease (PD). The funding was awarded under the Novel Approaches to Drug Discovery for PD program made possible by funding from Elan Corporation, a neuroscience-based biotechnology company.
Full text. In partnership with Arecor and the University of Colorado School of Pharmacy, PATH published findings in this month’s issue of Human Vaccines (volume 5, issue 8) that describe a new hepatitis B vaccine formulation exhibiting nine week stability at 55°C and at least six month stability at both 37°C and 45°C. The data indicate that the new hepatitis B vaccine formulation will be better able to withstand disruption in the cold chain and could potentially be stored at room temperature for a significant part of its shelf life.
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